The proper functioning of CNS neurons relies on complex and highly specific integration of synaptic inputs along their dendritic trees. The striatum is largely made up of two populations of medium sized GABAergic neurons characterized by densely spiny dendrites and differential expression in dopamine receptors immunoreactivity (D1 versus D2). The cerebral cortex and the thalamus are the two main sources of excitatory glutamatergic afferents to striatal medium spiny neurons (MSN). Together, these two afferents contribute more than 30,000 glutamatergic synapses onto individual striatal projection neurons. Midbrain dopaminergic inputs from the substantia nigra pars compacta (SNc) play a critical role in modulating glutamatergic transmission in the striatum. Consequently, lesion of this system results in significant neurochemical, electrophysiological and morphological changes in striatal MSNs in Parkinson's disease. The vesicular glutamate transporters 1 and 2 (vGluTI and vGluT2) are invaluable tools to label specifically the corticostriatal and thalamostriatal systems, respectively. Although these two striatal inputs have long been established, very little is known about the differential organization of the synaptic microcircuitry of these two pathways in normal and pathological basal ganglia conditions, largely because of the lack of specific markers to differentiate thalamic from cortical afferents in the striatum. For the past 15 years, our laboratory has been at the forefront of research to characterize the organization of synaptic microcircuits in primate basal ganglia. Our work has led to significant advancement in our understanding of the functional anatomy, synaptic connectivity and potential roles of the thalamostriatal system in monkeys. In this project, we propose to use vGluTI and vGluT2 as specific markers of corticostriatal and thalamostriatal terminals to further understand the functional organization and synaptic plasticity of these two pathways in normal monkeys and animal models of Parkinson's disease. Three main hypotheses will be addressed using high resolution electron microscopy immunocytohemistry combined with 3D reconstruction of dendritic spines in normal and MPTP- treated monkeys. Results of these studies will shed light on the substrates the underlie the synaptic mechanisms by which thalamic and cortical glutamatergic afferents control the activity of striatofugal neurons in both normal and pathological basal ganglia conditions.